Regorafenib shows a 37% reduction in risk of death in hepatocellular carcinoma

Regorafenib, an oral multikinase inhibitor, was found by new research to be effective and safe in patients with HCC who progress on prior sorafenib treatment, leading to a statistically significant and clinically meaningful improvement in overall survival (OS).

A 37% reduction in the relative risk of death was seen in the regorafenib group compared with placebo (hazard ratio (HR) 0.63; p<0.001). The median OS was 10.6 months and 7.8 months with regorafenib and placebo respectively.

“Survival was very positive as were the secondary endpoints.” Dr. Jordi Bruix, MD, principal investigator of the RESORCE trial, and Head of the Hepatic Oncology Unit at Hospital Clínic de Barcelona, Spain.

Dr Jordi Bruix, Principal Investigator of the RESORCE trial, and Head of the Hepatic Oncology Unit at Hospital Clínic de Barcelona, Spain, reported the results of efficacy, safety and health-related quality of life (HRQoL). “Survival was very positive, as were the secondary endpoints.”

OS was significantly improved, time to progression (TTP) was delayed and progression free survival (PFS) was improved. “This was all based on delay of tumour progression. The same tumour progression was observed whether measured by modified RECIST or RECIST. Survival was improved by over 37% which is statistically significant and clinically significant.”

Regorafenib is already approved for treatment-refractory metastatic colorectal cancer and gastrointestinal stromal tumours, and has shown anti-tumour activity in a phase II trial of patients with HCC who progressed during sorafenib treatment. “We felt there was a hint of efficacy in this phase II study and then we jumped into the phase III study,” commented Dr Bruix.

Reflecting on where regorafenib might fit into the treatment protocol, he explained that patients can be treated with transcatheter arterial chemoembolisation (TACE) if they have intermediate stage HCC with preserved liver function. “But when TACE does not induce necrosis, or after several rounds of TACE, disease control is not achieved, patients can transition into systemic therapy,” added Dr Bruix.

In such patients, the only available systemic therapy shown to improve OS has been sorafenib. Unfortunately, all phase III trials of novel systemic therapies for HCC have failed to improve outcomes in first- or second-line settings, and there are no proven or approved second-line systemic treatment options for HCC.

In the phase III RESORCE trial, patients with HCC were randomised to receive regorafenib (n=379; 160 mg orally once daily 3 weeks on/1 week off in a 4-week cycle) or placebo (n=194). The trial was conducted in 21 countries worldwide. Patients were stratified by geographic region (Asia vs rest of world); macrovascular invasion, extrahepatic disease; ECOG performance status (0 vs 1) and alpha-fetoprotein.

“The study targeted patients who would have received sorafenib, tolerated it but then progressed,” explained Dr Bruix. “But the criteria for tolerance of sorafenib were strict because we wanted to avoid having patients who only took a couple of doses entering the trial.”

OS provided the primary efficacy endpoint, while TTP, PFS, response rate and disease control rate were secondary. HRQoL was assessed by the Functional Assessment of Cancer Therapy Hepatobiliary (FACT-Hep), EQ-5D-3L and EQ-5D VAS questionnaires.

In addition to the encouraging OS results, regorafenib also improved PFS (HR 0.46; P<0.001), with a median PFS of 3.1 months with regorafenib and 1.5 months with placebo, TTP had a HR of 0.44 (p=0.001). The regorafenib group also had a significantly higher response rate (11% vs 4%; p=0.009).

Quality of life was similar in both arms and no evidence of deterioration of quality of life was found, reported Dr Bruix. “Effectively, this is a surrogate for the acceptability of the adverse effects, that can be managed by dose reduction, although over half of patients had the full dose.”

Adverse events were similar to those experienced on sorafenib, including hand-foot skin reaction, fatigue, hypertension, diarrhoea and some ascites. “We know that dermatological adverse events tend to correlate with better outcomes. We acknowledge that this shows the development of adverse events correlates with [efficacious] results so it is better to adjust the dose, adhere to it and benefit from it.”

The next step in making regorafenib more widely available is approval for second-line use after sorafenib, and then consideration should be given to combinations and sequential treatment starting with sorafenib and later regorafenib, and later still with immunotherapy potentially, concluded Dr Bruix.

Based on Bruix J, Merle P et al. Efficacy, safety, and health-related quality of life (HRQoL) of regorafenib in patients with hepatocellular carcinoma (HCC) progressing on sorafenib: Results of the international, double-blind phase 3 RESORCE trial (LBA28). Presented on Saturday 8 October 2016.

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